Summary Sleep is necessary for optimal cognitive function. There is broad consensus that insufficient sleep leads to a general slowing of response speed and increased variability in measures of alertness, attention, and vigilance. Accumulating evidence demonstrates that sleep deprivation (SD) negatively impacts higher level cognitive capacities, including memory and executive functions, and these cognitive disturbances are beyond those produced by impaired response and attention processes. Memory consolidation is known to be influenced by SD and our feasibility evidences strongly suggest dietary supplementation with specific botanical supplement mixtures (grape seed extract, Concord grape juice and resveratrol) significantly promoted resilience to cognitive dysfunction in the context of SD. We have also identified that a number of phenolic metabolites, derived from these bioactive botanical supplement mixtures that accumulate in brain tissues, are capable of modulating synaptic plasticity through two independent yet interrelated pathways, one mediated through activation of CREB signaling and the other through induction of immediate early genes (IEGs) expression. Our innovative proposal will test the overarching hypothesis that select brain-penetrating phenolic metabolites have a protective effect in promoting resilience to SD-induced cognitive dysfunction through comparative in vitro and in vivo assessments. The proposed project will mechanistically investigate the role of the grape-derived botanical supplement mixtures in modulating synaptic plasticity in a mouse model of SD with the goal of testing the ability of select brain-available phenolic metabolites in promoting resilience to SD-induced cognitive deficits through activation of the CREB signaling pathway (Aim 1) and modulation of IEG expression (Aim 2). In collaboration with Project 3, we will also test whether the application of novel probiotics specifically designed to promote conversion of metabolites identified in Aims 1-2 studies can maximize the effect of bioactive botanical supplement mixtures on promoting resilience to SD-induced cognitive dysfunction (Aim 3). The protective effect of the phenolic metabolites, evaluated through behavioral cognition tests in mouse models of sleep deprivation, will provide alternative translational approaches to promote cognitive integrity in the context of SD.